Analgesic composition and method of making the same

ABSTRACT

A soluble aspirin composition, comprising: (i) granules including aspirin, heat-treated bicarbonate salt, pharmaceutically-acceptable resin and surfactant, in mixture with: (ii) crystalline particles of pharmaceutically-acceptable acid; and (iii) crystalline particles of heat-treated bicarbonate salt; wherein the soluble aspirin composition when introduced to water undergoes reaction of the crystalline particles of pharmaceutically-acceptable acid with the heat-treated bicarbonate salt and the aspirin to effect effervescing action and disintegration of the granules with conversion of the aspirin to an acetylsalicylate compound of the bicarbonate salt cation so that the composition rapidly dissolves in the water without occurrence of undissolved residue. The composition is solubilizable within 30 seconds in cool to cold water to provide an effervescent analgesic solution that can be readily orally administered to an individual in need of analgesia.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation under 35 USC 120 of U.S. patentapplication Ser. No. 13/158,544, filed Jun. 13, 2011. The disclosure ofthe U.S. patent application Ser. No. 13/158,544 is hereby incorporatedherein by reference in its entirety for all purposes.

FIELD

The present disclosure relates to analgesic compositions and methods ofmaking and using the same. More specifically, the disclosure relates toa soluble aspirin analgesic composition having improved dose forms,taste, ease-of-use and aqueous solubility characteristics.

DESCRIPTION OF THE RELATED ART

Approximately 84% of the U.S. population regularly uses non-prescriptionanalgesics for minor pain relief for conditions such as headache, muscleache or backache. Over $2 billion worth of such analgesics are soldannually by supermarkets, drugstores and mass merchandisers.

The non-prescription analgesics market encompasses pain-reliefmedications having four principal active chemical ingredients, aspirin,acetaminophen, ibuprofen and naproxen sodium. Brand names arewell-established in each of these segments, and include Tylenol(acetaminophen), Advil and Motrin (ibuprofen), Aleve (naproxen sodium),Bayer (aspirin or combination), Excedrin (acetaminophen), Midol andPamprin (varied formulas for menstrual pain relief).

Aspirin has a number of inherent advantages. Like other pain relieversof the type discussed above, aspirin is effective for treatment of pain,fevers, arthritis, and headaches, but unlike such other analgesicproducts, aspirin is the only pain reliever shown to reduce the risk ofheart attack. In addition, aspirin is the oldest and best established ofthe common pain relievers, with well over a century of use throughoutthe world.

In the field of aspirin pain relievers, effervescent soluble aspirinproducts such as Aspro or Disprin are quite popular in other countriessuch as Australia, Canada, Great Britain and New Zealand. In the U.S.,Alka-Seltzer, an effervescent formulation including aspirin, sodiumbicarbonate and citric acid. Alka-Seltzer is the world's number one curefor hangover and is currently sold in over 100 countries, generatingannual sales in excess of $100 million. Overall, the soluble aspirinproducts market worldwide exceeds $2 billion.

The first-generation soluble aspirin products began to appear at thebeginning of the last century. See, for example, U.S. Pat. No. 740,703issued in 1903. These early products were based on various solublesalts, lithium, sodium, potassium, calcium and magnesium as well as withorganic amines and amino acids (lysine and ormthine), and were notstable formulations. Their instability resulted from water ofcrystallization contained in the salts, that resulted in degradation ofaspirin into salicylic and acetic acids. Efforts to improve suchproducts focused on removal of the water of crystallization, andformation of anhydrous salts, but the resulting compositions weredifficult to handle and expensive to produce, involved unsuitably highlevels of metallic elements, and were not economically competitiveagainst aspirin.

Later developments in such first-generation products employed bufferingcoatings intended to neutralize gastric acidity. Clinical studiesshowed, however, that is not possible to coat aspirin tablets withsufficient amounts of buffering agent to totally neutralize gastricacid, and such buffering coatings are ineffective in preventing insoluble aspirin particles from adhering to gastrointestinal mucosa.Enteric coatings have been alternatively utilized, but are subject tothe same mucosal adhesion problems in the intestinal locus.

Subsequent first-generation soluble aspirin products include productsbased on soluble salts of aspirin, such as that disclosed in U.S. Pat.No. 3,985,792, in which aspirin is reacted with sodium bicarbonate andwater to form a sodium salt solution that then is treated with alcoholand cooled to crystallize sodium acetylsalicylate dihydrate. Thisdihydrate then is filtered, washed and dehydrated to provide the finalproduct. Such product is, however, extremely susceptible to degradationby moisture, and additionally requires large amounts of alcohol thatmust be separated by distillation.

The shortcomings of the first generation products were addressed in asecond-generation formulation of soluble aspirin developed by thepresent inventor and more fully described in U.S. Pat. No. 5,723,453.This second-generation product was a stabilized, essentially sodium-freeaspirin composition that was readily soluble in aqueous medium. Itcomprised aspirin granules of predetermined particle size and granularpotassium bicarbonate.

Although the soluble aspirin composition of U.S. Pat. No. 5,723,453achieved improvements over earlier soluble aspirin formulations withrespect to taste and dissolution rate, it was nonetheless characterizedby some degree of residue and slowed dissolution rate in cold water orother lower temperature aqueous medium, relative to dissolution rate inaqueous media at room temperature ambient conditions.

The art accordingly continues to seek improvement in aspirincompositions, in respect of their dose forms, taste, ease-of-use,dissolution rate and completeness of dissolution in aqueous media.

SUMMARY

The present disclosure relates to a soluble aspirin analgesiccomposition and methods of making and using same.

In one aspect, the disclosure relates to a soluble aspirin composition,comprising: (i) granules including aspirin, heat-treated bicarbonatesalt, pharmaceutically-acceptable resin and surfactant, in mixture with:(ii) crystalline particles of pharmaceutically-acceptable acid; and(iii) crystalline particles of heat-treated bicarbonate salt; whereinthe soluble aspirin composition when introduced to water undergoesreaction of the crystalline particles of pharmaceutically-acceptableacid with the heat-treated bicarbonate salt and the aspirin to effecteffervescing action and disintegration of the granules with conversionof the aspirin to an acetylsalicylate compound of the bicarbonate saltcation, so that the composition rapidly dissolves in the water withoutoccurrence of undissolved residue.

The disclosure in another aspect relates to a dry solids aspirincomposition, comprising: (i) granules including aspirin, heat-treatedpotassium bicarbonate, pharmaceutically-acceptable resin and surfactant,in mixture with: (ii) crystalline particles ofpharmaceutically-acceptable acid; and (iii) crystalline particles ofheat-treated potassium bicarbonate.

In a further aspect, the disclosure relates to a method of making asoluble aspirin composition, comprising: agglomerating powdered aspirinand powdered heat-treated bicarbonate salt with apharmaceutically-acceptable resin and surfactant, to form granules; andmixing the granules with crystalline particles ofpharmaceutically-acceptable acid and crystalline particles ofheat-treated bicarbonate salt, to yield the soluble aspirin analgesiccomposition.

The disclosure in a still further aspect relates to a method ofproviding aspirin treatment to a subject in need thereof, comprisingmixing an effective amount of the dry solids aspirin composition ofclaim 13 with a solubilizing quantity of aqueous medium, to produce asolubilized aspirin solution, and administering said solubilized aspirinsolution to said subject.

As used herein, the term “bicarbonate salt” refers to a pharmaceuticallyacceptable salt compound including a bicarbonate anion. The cationiccomponent of the salt compound may for example comprise one or more ofpotassium, sodium, calcium, magnesium, lithium, or any other suitablecation species. A preferred bicarbonate salt in the compositions, doseforms, and methods of the disclosure is potassium bicarbonate. While thedisclosure hereinafter is primarily directed to potassium bicarbonate asan exemplary bicarbonate salt, it will be recognized that the disclosureis not thus limited, but rather is intended to be broadly construed andto encompass any pharmaceutically acceptable bicarbonate compoundshaving useful cationic moieties in the compositions, dose forms andmethods of the disclosure.

As used herein, the term “heat-treated” in reference to the bicarbonatesalt refers to a bicarbonate salt that has been subjected to elevatedtemperature sufficiently long enough to impart to it a pH in a range offrom 8.4 to 10.0. Such heat treatment involves at least partialconversion of the bicarbonate to a carbonate. Specific pH ranges invarious embodiments of the disclosure can include pH in a range of from8.5 to 9.7, more preferably a pH in a range of from 8.9 to 9.6, and mostpreferably a pH of about 9.5. In various applications, the heat-treatedbicarbonate salt may have a pH in a range with a lower end point that invarious embodiments may be 8.5, 8.6, 8.7, 8.8, or 8.9, and with an upperend point that in various embodiments may be 9.1, 9.2, 9.3, 9.4, 9.5,9.6, 9.7, 9.8 or 9.9, it being appreciated that any of such single lowerpoint values and single upper point values may in such variousembodiments delimit specific ranges of pH within which the disclosuremay be practiced.

As used herein, the term “water-soluble” refers to aqueous solubility,and encompasses the solubility categories of “very soluble,”“freely-soluble,” “soluble” and “sparingly soluble,” as described inRemington's Pharmaceutical Sciences and Remington: Practice of Pharmacy.

Other aspects, features and embodiments of the disclosure will be morefully apparent from the ensuing description and appended claims.

DETAILED DESCRIPTION

The present disclosure relates to an analgesic composition and methodsof making and using the same, having aspirin as an active ingredient, ina form having appealing taste, ease-of-use, dissolution rate andcompleteness of dissolution in aqueous media.

The present disclosure is based on the discovery that an extremely quickand residue-free dissolution of aspirin can be effected, when theaspirin is incorporated in granules containing powdered heat-treatedbicarbonate salt, pharmaceutically-acceptable resin, and surfactant,with such aspirin-containing granules being provided in mixture withcrystalline particles of pharmaceutically-acceptable acid andcrystalline particles of heat-treated bicarbonate salt. In suchcomposition containing aspirin-incorporating granules and freecrystalline particles of acid and bicarbonate salt, the free acidcrystals react with the free bicarbonate salt crystals to establish anintense initial effervescence, while at the same time, the free acidcrystals react with bicarbonate salt in the granules, to likewiseproduce an intensive reaction that causes the granules to rapidlyfragment and expose new surface containing the bicarbonate salt, whichthereupon intensively reacts with the acid crystals to effect furtherfragmentation and disintegration of the granule fragments. The reactioninvolves the formation of potassium acetylsalicylate from the aspirin inthe granules, with the potassium acetylsalicylate immediately dissolvingin the aqueous medium without residue being formed.

The granules thus include aspirin, powdered heat-treated bicarbonatesalt, resin and surfactant. Such granules by themselves are susceptibleto dissolution in the aqueous medium to which the granules areintroduced, but the presence of the free crystals ofpharmaceutically-acceptable acid and free crystals of heat-treatedbicarbonate salt greatly accelerate the reaction of the powderedheat-treated bicarbonate salt and aspirin in the granules so thatextremely rapid dissolution of all ingredients of the composition isachieved, e.g., in less than 60 seconds, without residue formation.

The composition of the present disclosure thus comprisesaspirin-containing and heat-treated bicarbonate salt-containinggranules, in mixture with crystals of a pharmaceutically-acceptable acidand crystals of heat-treated bicarbonate salt. The composition may beformulated with any suitable relative amounts and proportions of thevarious ingredients in relation to one another, as effective to providedissolution the composition in aqueous medium within 60 seconds withoutresidue formation, and as effective to provide aspirin treatment to asubject, e.g., a human subject or a non-human mammalian subject, upondrinking or other administration of such aqueous medium containing thedissolved composition of the disclosure.

In one aspect, the disclosure relates to a soluble aspirin composition,comprising: (i) granules including aspirin, heat-treated bicarbonatesalt, pharmaceutically-acceptable resin and surfactant, in mixture with:(ii) crystalline particles of pharmaceutically-acceptable acid; and(iii) crystalline particles of heat-treated bicarbonate salt; whereinthe soluble aspirin composition when introduced to water undergoesreaction of the crystalline particles of pharmaceutically-acceptableacid with the heat-treated bicarbonate salt and the aspirin to effecteffervescing action and disintegration of the granules with conversionof the aspirin to an acetylsalicylate compound of the bicarbonate saltcation, so that the composition rapidly dissolves in the water withoutoccurrence of undissolved residue.

Such soluble aspirin composition can be formulated in which thebicarbonate salt comprises one or more of potassium bicarbonate, sodiumbicarbonate, calcium bicarbonate, magnesium carbonate and lithiumcarbonate.

Aspirin may be present in such composition at a concentration of from 50to 2000 mg. The composition can be formulated so that the heat-treatedbicarbonate salt comprises heat-treated potassium bicarbonate having apH in a range of from 8.4 to 10. In the compositions of the disclosure,the pharmaceutically-acceptable resin can be selected from the groupconsisting of polyvinyl pyrrolidone, polyvinyl alcohol, acrylic acidpolymers, methacrylic acid polymers, sulfonated styrenes, sulfonateddimethyl benzenes, modified celluloses, and dextrans. In variousembodiments, the pharmaceutically-acceptable resin comprises polyvinylpyrrolidone.

The pharmaceutically-acceptable resin in various compositions of thedisclosure can have a concentration in a range of from about 1.5 toabout 4 percent by weight, based on total weight of the granules. Thepharmaceutically-acceptable acid in the compositions of the disclosurecan be of any suitable type, and can for example be selected from thegroup consisting of citric acid, acetic acid, adipic acid, benzoateacid, caproic acid, malic acid, malonic acid, nicotinic acid, lauricacid, glycolic acid, oxalic acid, phosphoric acid, succinic acid, oleicacid, palmitic acid, proprionic acid, cinnamic acid, gluconic acid,stearate acid, and tartaric acid.

The surfactant in the compositions of the disclosure can be of anysuitable type and can for example be selected from the group consistingof sodium laurel sulfate, polyoxyethylene sorbitan monolaurate,polyoxyethylene sorbitan monooleate, polyethylene glycol 300,propoxylated polyethylene glycol, polyoxyethylene lauryl ether, anddiethylene glycol monoethyl ether. In one embodiment, the surfactantcomprises sodium laurel sulfate at a concentration in a range of from0.01 to 0.1 weight percent, based on total weight of the granules.

Various compositions of the disclosure can be constituted to include atleast one ingredient selected from the group consisting of flavorants,sweeteners, acetaminophen (paracetamol), and caffeine. The compositionsof the disclosure can be formulated in various embodiments to beoil-free in character, and to have a moisture content less than 0.5% byweight, based on total weight of the composition.

Another aspect of the disclosure relates to a dry solids aspirincomposition, comprising: (i) granules including aspirin, heat-treatedpotassium bicarbonate, pharmaceutically-acceptable resin and surfactant,in mixture with: (ii) crystalline particles ofpharmaceutically-acceptable acid; and (iii) crystalline particles ofheat-treated potassium bicarbonate.

Such dry solids aspirin composition may be formulated to include aspirinat a concentration of from 50 to 2000 mg. In specific embodiments, pH ofthe heat-treated potassium bicarbonate can be in a range of from 8.4 to10. The pharmaceutically-acceptable resin in various embodiments cancomprise polyvinyl pyrrolidone. The pharmaceutically-acceptable resincan have any suitable concentration, e.g., a concentration in a range offrom about 1.5 to about 4 percent by weight, based on total weight ofthe granules. The pharmaceutically-acceptable acid can be of anysuitable type in the dry solids aspirin composition, and can for examplebe citric acid, wherein the surfactant in the composition comprisessodium laurel sulfate.

The dry solids aspirin composition can be formulated to include at leastone ingredient selected from the group consisting of flavorants,sweeteners, acetaminophen and caffeine. In a specific implementation,the dry solids aspirin composition is oil-free in character, and hasmoisture content less than 0.5% by weight, based on total weight of thecomposition.

The disclosure in another aspect contemplates a method of making asoluble aspirin composition, comprising: agglomerating powdered aspirinand powdered heat-treated bicarbonate salt with apharmaceutically-acceptable resin and surfactant, to form granules; andmixing the granules with crystalline particles ofpharmaceutically-acceptable acid and crystalline particles ofheat-treated bicarbonate salt, to yield the soluble aspirin analgesiccomposition.

A further aspect of the disclosure relates to a method of providingaspirin treatment to a subject in need thereof, comprising mixing aneffective amount of the dry solids aspirin composition of claim 13 witha solubilizing quantity of aqueous medium, to produce a solubilizedaspirin solution, and administering said solubilized aspirin solution tosaid subject. In such method, the aqueous medium may comprise water orother aqueous liquid. The method of aspirin treatment can be conductedto provide treatment of one or more of headache, migraine, rheumaticpains, neuralgia, menstrual pain, toothache, and symptoms of colds andinfluenza.

Thus, the soluble aspirin composition of the disclosure in variousembodiments includes powdered aspirin and powdered heat-treatedbicarbonate salt, agglomerated together with apharmaceutically-acceptable resin and surfactant, to constitutegranules. The granules can be used to formulate dry solids dose forms,as a mixture of the granules with crystalline particles ofpharmaceutically-acceptable acid and crystalline particles ofheat-treated bicarbonate salt.

In one preferred embodiment, the bicarbonate salt in the granules and inthe crystalline particles is potassium bicarbonate. It will beappreciated that the bicarbonate salt in the granules and in thecrystalline particles may be the same as, or alternatively differentfrom, one another.

The composition of the disclosure thus can be provided in the form of adry solids mixture, as a dose form that is readily soluble in an aqueousmedium, e.g., water or a water-containing liquid medium.

The dry solids analgesic dose form of the disclosure can be formulatedto provide any suitable concentration of the aspirin active ingredient,e.g., a concentration of from 50 mg to 2000 mg. In various embodiments,the aspirin active ingredient may be present in an amount, measured inmilligrams, in a range with a lower end point of 80, 100, 200, 250, 300,400, 500 or 600, and with an upper end point that in various embodimentsmay be 700, 800, 1000, 1200, 1400, 1500, 1600, or 1800, it beingappreciated that any of such single lower point values and single upperpoint values may in such various embodiments delimit specific ranges ofaspirin concentration within which the disclosure may be practiced. Inone embodiment, the composition contains aspirin in an amount of 81 mg.

The aspirin used in the composition of the disclosure may have anysuitable particle size and particle size distribution. The aspirin mayfor example have a mesh size in a range of from 8 to 350 mesh. Invarious embodiments, the aspirin ingredient may have a mesh size in arange with a lower end point of 10, 20, 30, 50, 75, 100, 125, 150, 175,200, 250 or 300, and with an upper end point that in various embodimentsmay be 310, 315, 320, 325, 330, 335, 340 or 345, it being appreciatedthat any of such single lower point values and single upper point valuesmay in such various embodiments delimit specific ranges of aspirin meshsize within which the disclosure may be practiced.

The compositions of the disclosure thus employ heat-treated bicarbonatesalt in two distinct forms, viz., in a granular form (in granulesincluding powdered heat-treated bicarbonate salt, e.g., potassiumbicarbonate, together with powdered aspirin, resin and surfactantingredients) and in a crystalline particle form. The heat-treatedbicarbonate salt in granular form can have any suitable particle sizeand size distribution characteristics. For example, in various specificembodiments, the heat-treated bicarbonate salt in the granules may havea mesh size in a range of from 10 to 325 mesh, while heat-treatedbicarbonate salt in crystalline particle form may have a mesh size in arange of from 8 to 350 mesh, a range of from 10 to 150 mesh, a range offrom 20 to 100 mesh, or any other suitable mesh size range.

In various embodiments, the heat-treated bicarbonate salt ingredient inthe respective granules and crystalline particles may have a mesh sizein a range with a lower end point of 12, 20, 30, 50, 75, 100, 125, 150,175, or 180, and an upper end point that in various embodiments may be200, 210, 220, 230, 250, 280, 300, 320, 330 or 350, it being appreciatedthat any of such single lower point values and compatible single upperpoint values may in various embodiments delimit specific ranges ofheat-treated bicarbonate salt mesh size within which the disclosure maybe practiced. In general, the bicarbonate salt may be widely varied incomposition in relation to the aspirin component. For example, invarious embodiments, the ratio of the bicarbonate salt to aspirin may bein a range of from about equimolar amounts of each of such ingredientsup to a ratio value of 4 or more.

The pharmaceutically-acceptable resin utilized in soluble aspirincompositions of the present disclosure may be of any suitablepharmaceutically-acceptable type, and may for example be selected fromamong polyvinyl pyrrolidone, polyvinyl alcohol, acrylic acid polymers,methacrylic acid polymers, sulfonated styrenes, sulfonated dimethylbenzenes, cellulosic, and modified cellulosic polymers (e.g.,hydroxypropylmethyl cellulose). Polyvinyl pyrrolidone is a preferredresin. The resin utilized in the composition may be present in specificembodiments of the formulation at any suitable concentration. In variousembodiments, concentration of the resin may be in a range of from about1.5 to about 4 percent by weight, and more preferably from about 1.8 toabout 3 percent by weight, based on total weight of the granules(aspirin, bicarbonate salt, resin and surfactant ingredients).

In other embodiments, the pharmaceutically-acceptable resin may have aconcentration in a range with a lower end point that in such embodimentsmay be 1.6%, 1.65%, 1.7%, 1.75%, or 1.8%, and with an upper end point of2.1%, 2.2%, 2.5%, 2.8%, 3.0%, 3.25%, 3.5%, 3.75%, or 3.8%, by weight,based on total weight of the granules.

In general, the amount of the pharmaceutically-acceptable resin is suchthat it is effective to effect agglomeration of the granules of powderedaspirin and powdered heat-treated bicarbonate salt, e.g., potassiumbicarbonate. Accordingly, the amount of resin in a specific embodimentmay vary depending on the type of resin employed, the type of surfactantemployed, and the agglomerative character of the powdered heat-treatedbicarbonate salt and powdered aspirin that are present in the granules.

The pharmaceutically-acceptable acid employed in compositions of thepresent disclosure likewise may be of any suitable type, and in specificembodiments can include one or more acids such as citric acid, aceticacid, adipic acid, benzoate acid, caproic acid, malic acid, malonicacid, nicotinic acid, lauric acid, glycolic acid, oxalic acid,phosphoric acid, succinic acid, oleic acid, palmitic acid, proprionicacid, cinnamic acid, gluconic acid, stearate acid, tartaric acid.Additional pharmaceutically-acceptable acids potentially useful in thecompositions of the present disclosure are described in P. H. Stall andC. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties,Selection and Use, Weinheim/Zurich: Wiley-VCH/VHCA, 2002. Citric acid isa preferred acid for such purpose, with citric acid anhydrous USP beingmost preferred. The anhydrous citric acid in one embodiment is pre-driedto low moisture content, e.g., less than 0.01% moisture content.

In general, the pharmaceutically-acceptable acid can be of any suitabletype that is reactive with the heat-treated bicarbonate salt in thecomposition. Such acid is advantageously present in solid crystal form,as crystalline particulate material, with large size acid crystals beinguseful in effecting break-up of the surface foam that would otherwise bepresent, by forming gas bubbles in the reaction, which act to break upsurface foam.

The specific amount of pharmaceutically-acceptable acid employed incompositions of the present disclosure is desirably selected to effectreaction with the crystalline particles of heat-treated bicarbonate saltpresent in the composition, to effect effervescing action in aqueousmedium that in turn assists in the break-up of the granules containingpowdered heat-treated bicarbonate salt and powdered aspirin, and furtherreaction of the heat-treated bicarbonate salt that is present in thegranules.

The pharmaceutically-acceptable acid may have any suitable mesh size,e.g., a mesh size in a range of 4-325 mesh, with a mesh size in a rangeof 5-100 mesh being preferred, a mesh size in a range of 5-40 mesh beingmore preferred, a mesh size in a range of 8-30 mesh being still morepreferred, and a mesh size in a range of from 8 to 14 mesh being mostpreferred. The mesh size of the pharmaceutically-acceptable acid may bein a mesh size range that in various embodiments has a lower end pointof 5, 5.5, 6, 6.5, 7, or 7.5 mesh, and an upper end point that invarious embodiments may be 35, 40, 45, 50, 60, 75, 80, 100, 120, 140,150, 160, 175, 180, 200, 220, 250, 280, 290 or 310 mesh, it beingappreciated that any of such single lower point values and compatibleupper single point values may be in various embodiments delimit specificranges of pharmaceutically-acceptable acid within which the disclosuremay be practiced.

Surfactants useful in the compositions of the present disclosure includepharmaceutically-acceptable surface active agents that are compatiblewith the other ingredients of the analgesic composition, and includesodium laurel sulfate, polyoxyethylene sorbitan monolaurate,polyoxyethylene sorbitan monooleate, polyethylene glycol 300,propoxylated polyethylene glycol, polyoxyethylene lauryl ether, anddiethylene glycol monoethyl ether. Sodium laurel sulfate is a preferredsurfactant species.

The surfactant may be employed in any suitable amount that is effectivefor good dissolution and effervescing action of the composition. Whileany suitable amount of surfactant may be employed, it has been foundadvantageous in various embodiments of the disclosure to utilizesurfactants in a concentration that is less than 0.1% by weight, basedon total weight of the granules. The surfactant in specific embodimentsmay have a concentration in a range of from 0.01 to 0.1 weight percent,based on total weight of the granules. In various embodiments, thesurfactant may have a concentration in a range with a lower end point of0.011, 0.012, 0.013, 0.014, 0.015, 0.020, 0.030, 0.040 or 0.045 weightpercent, based on total weight of the granules, and an upper end pointthat in various embodiments may be 0.050, 0.060, 0.070, 0.080, 0.090 or0.095 weight percent, based on total weight of the granules. It willalso be appreciated that any of such single lower point values andcompatible single upper point values may in various embodiments delimitspecific ranges of surfactant concentration within which the disclosuremay be practiced.

In various specific embodiments, the amount of the surfactant based onthe total weight of the soluble aspirin composition may be on the orderof about 0.05 weight percent or less, based on total weight of thecomposition, e.g., in a range of from about 0.005 weight percent toabout 0.05 weight percent.

The resin and surfactant preferably are dissolved in apharmaceutically-acceptable solvent and then combined with the powderedaspirin and powdered heat-treated bicarbonate salt ingredients in a highor low shear granulator or a fluid bed granulator. The solvent can be ofany suitable type, e.g., and may include one or more solvent speciesselected from among alcohols, ethers, glycols, glycol ethers,N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), glycerol,1,2,-propylene-diol (PG), and polyethylene glycols. Preferred solventsinclude alcohols, with isopropyl alcohol being most preferred. Ingeneral, the amount of solvent employed is minimized, as the amountnecessary to dissolve the resin and surfactant ingredients of thecomposition and provide a resulting solution amenable to combinationwith the powdered aspirin and powdered bicarbonate salt ingredients, forthe purpose of effecting granulation.

Compositions of the disclosure, in addition to the aspirin, bicarbonatesalt, pharmaceutically-acceptable acid, pharmaceutically-acceptableresin and surfactant ingredients, can comprise additional activeingredients, flavorants, solubilizers, stabilizers, anti-oxidants,and/or other excipients. For example, the composition may contain avasomodulator, such as a methylxanthine, e.g., caffeine, or other activeingredient(s), e.g., acetaminophen, and/or flavorants, sweeteners andsimilar ingredients, e.g., Sucralose™ sweetener, Aspartame™ sweetener,vanillin, etc. Flavorants are preferably spray-dried or otherwisepre-dried to less than 0.5% moisture content. The flavor ingredients areadvantageously oil-free in character, to provide high ratesolubilization of the composition in aqueous medium, without theoccurrence of a surface layer of undissolved particulate components orother residue after the dry solids analgesic composition has been addedto water or other aqueous medium.

Specific flavor ingredients include flavorants commercially availablefrom Givauden S.A. (Vernier, Switzerland) under the trademarksTasteEssentials™, TasteSolutions™, ByNature™, and PureDelivery™. In oneembodiment, the flavorants are blended with Sucralose™ and vanillincrystals. In other embodiments, flavors can be varied by differentgranulations of suitable flavors, such as fruit flavors (peach, cherry,etc.).

In one embodiment, the soluble aspirin analgesic composition of thedisclosure comprises substantially equal amounts of aspirin andacetaminophen, and optionally caffeine. For example, an illustrativecomposition of such type may contain 325 mg of the soluble aspirin, and325 mg of acetaminophen powder. More generally, aspirin andacetaminophen may be present in the composition in any suitable amountsor ratios in relation to one another. In a specific embodiment, each ofthe aspirin and acetaminophen ingredients is present in an amount thatis within a range of from 50 mg to 500 mg. In another specificembodiment, each of the aspirin and acetaminophen ingredients is presentin an amount of 81 mg.

The compositions of the disclosure preferably are in a substantiallyanhydrous state, as a dry solid particulate material, e.g., having awater/moisture content less than 0.5% by weight, based on the weight ofthe composition, more preferably less than 0.3% by weight, and mostpreferably less than 0.1% by weight, on the same composition weightbasis. The composition also is advantageously completely oil-free incharacter, to maximize compatibility of the composition with water orother aqueous medium.

The soluble aspirin analgesic composition of the disclosure may beformulated in any suitable manner producing the granules of powderedaspirin and powdered heat-treated bicarbonate salt, in mixture withcrystalline particles of pharmaceutically-acceptable acid andcrystalline particles of heat-treated bicarbonate salt.

The crystalline particles of heat-treated bicarbonate salt may beprovided in any appropriate amount in relation to the powderedbicarbonate salt that is in the granules of the composition. Specificrelative proportions may be readily determined for use without undueexperimentation, within the skill of the art, based on the disclosureherein. In various specific embodiments, the amount of the crystallineparticle heat-treated bicarbonate salt can be in a range of from 0.1 to5.0 times the amount of powdered heat-treated bicarbonate salt in thegranules of the composition. More typically, the amount of theheat-treated bicarbonate salt in the crystalline particles in thecomposition is in a range of from 0.25 to 0.75 times the amount of theheat-treated bicarbonate salt in the granules of the composition.

In one embodiment, the composition of the disclosure includes 650milligrams powdered aspirin and 750 milligrams powdered heat-treatedpotassium bicarbonate in the granules of the composition, in mixturewith 300 milligrams of heat-treated crystalline particles of potassiumbicarbonate, and 300 milligrams of anhydrous crystalline particles ofcitric acid. In such embodiment, the granules are formed usingpolyvinylpyrrolidone and sodium laurel sulfate in isopropanol, and thecomposition further contains 80 milligrams of sweetener and flavoringredients.

In such illustrative composition, the heat-treated potassium bicarbonatein particulate crystalline form can have a mesh size in a range of from20 to 60 mesh. The heat-treated powdered potassium bicarbonate in thegranules can have a mesh size on the order of 200 mesh, and the powderedaspirin in the granules can have a mesh size on the order of 325 mesh.Such illustrative composition is oil-free and dry, having a moisturecontent of less than 0.5% moisture by weight, based on weight of thecomposition.

The method of making the soluble aspirin analgesic composition of thedisclosure, in one embodiment thereof, includes the steps of:agglomerating powdered aspirin and powdered heat-treated bicarbonatesalt with a pharmaceutically-acceptable resin and surfactant, to formgranular solids; and mixing the granular solids with crystallineparticles of pharmaceutically-acceptable acid and crystalline particlesof heat-treated bicarbonate salt, to yield the soluble aspirin analgesiccomposition.

The soluble aspirin analgesic composition of the disclosure isadvantageously provided as a dry solids mixture that is readily solublein aqueous medium such as water. The composition may for example bepackaged in a packet, bag, vial or other container, to which water orother aqueous medium may be added, to provide an effervescent analgesicsolution that is orally administerable to a subject (e.g., human, dog,cat, or other animal) in need of analgesia.

The soluble aspirin analgesic compositions of the disclosure are highlystable in character, quickly dissolve in water or other aqueous medium,and leave no or negligible residue. The effervescent analgesic solutionthat is produced by mixing the analgesic composition with an aqueousmedium, is highly effective in producing analgesia.

The composition of the disclosure, in one embodiment thereof, includesthe following ingredients: potassium bicarbonate, USP granular;potassium bicarbonate, USP milled; aspirin, USP milled; sweetener; spraydried flavors; citric acid anhydrous, USP; flavoring; surfactant;pharmaceutically-acceptable carrier resin; alcohol; acetaminophen; and,optionally, caffeine.

These ingredients in raw material form may be pretreated by drying toachieve a moisture content of less than 0.5%, if the material is notalready dried to such extent. All solid ingredients are delumped andscreened. Potassium bicarbonate materials starting materials are heattreated, e.g., to raise pH level thereof to suitable level in a pH rangeof from 8.4 to 10, e.g., a pH value in a range of 8.5 to 9.7, morepreferably a pH value in a range of 8.9 to 9.6, and most preferably a pHvalue in the vicinity of pH 9.5. The carrier resin and surfactant aredissolved in a minimum amount of solvent so that the resultingcomposition can be combined with the powdered heat-treated bicarbonatesalt and powdered aspirin to form the granules.

The heat treating, blending, packaging and other processing steps may becarried out with appropriate machinery within the skill the art, basedon the disclosure herein. In one embodiment, such machinery may includea twin cone vacuum rotating dryer equipped with a heating jacket, agranulator, a vacuum pump drier, a solids mill, a pH monitoring device,as well as sealable storage containers, and a supply of steam or hotoil.

In the granulation operation, a high shear granulator/vacuum dryer ispreferably used. Other options include use of a high or low sheargranulator in combination with a closed circuit fluid bed dryer withsolvent recovery capability or vacuum drying with solvent recovery. Aperistaltic pump liquid binder delivery system can be employed, with abinder mixing tank and agitator. Blending operations may be carried outwith a slant cone blender or other appropriate blending machine. Highshear mixing may be conducted with appropriate high shear mixers inmilling and other mixing operations.

The ingredients of the soluble aspirin composition of the disclosure areadvantageously processed so that the constituent particles therein arenon-floating in character, when the dry solids composition is mixed withwater or other aqueous medium.

Packaging may be carried out with vertical form/fill/seal stickpackaging machines equipped with an inert gas purge, and conventionalbox packaging and case packaging equipment may be employed.

In the granulation process, heat-treated bicarbonate salt, aspirin andoptionally caffeine may be processed in a high shear mixer. Suchingredients may be sized to avoid breaking any of the granules down topowder. The carrier resin and surfactant are dissolved in apredetermined minimum amount of the pharmaceutically-acceptable solventto form a binder solution. With the choppers and mixing blade of thegranulator set at appropriate speed, the binder solution is added andgranulation is continued until a desired small particle size and highdensity of granules is achieved. When granulation is completed, heat andvacuum are applied to dry the granulated mixture to a suitably lowmoisture content, e.g., a moisture content in a range of from 0.05% to0.5% moisture content. The granulated mixture then is milled to asuitable particle size, e.g., in a range of from 12 to 100 mesh, morepreferably in a range of 25 to 75 mesh.

In the manufacturing operation, the granules are kept small and dustfree. This is important in providing effective solubilization characterof the final product. Excessively large granules will float to thesurface of the aqueous dissolution medium and take longer to dissolve,leaving undissolved particles on the side of the container of theaqueous medium. An excessively small granule size will not achieve adesired mixture of all granulated ingredients, and will not dissolveproperly (i.e., undissolved ingredients will be left as a residue). Theparticular size of the granules containing the heat-treated bicarbonatesalt, aspirin, resin and surfactant can be readily empiricallydetermined without undue effort for a given application of thedisclosure, within the skill of the art, based on the disclosure herein.

Flavor, sweetener and pharmaceutically-acceptable acid ingredients aredelumped and preblended together to form a preblended mixture beforefinal blending. In final blending, the granulated mixture, containingthe aspirin and heat-treated bicarbonate salt, is mixed with thepreblended mixture and heat-treated crystalline particles of bicarbonatesalt, and optionally additional heat-treated granular bicarbonate salt.The resulting blended product then is packaged for subsequent use.Packaging may for example be carried out under nitrogen purging, withthe product being introduced into sealed stick packs.

The soluble aspirin composition of the disclosure comprises a granulatedportion of aspirin and bicarbonate salt, in a finely granulated form,and a blended portion of pharmaceutically-acceptable acid crystals andheat-treated bicarbonate salt crystals, which react immediately whenexposed to water, thereby breaking down the granules in the composition.Such composition thus includes granules containing heat-treatedbicarbonate salt, as well as free-form crystalline particles ofheat-treated bicarbonate salt.

The compositions of the disclosure can contain any suitable dosage ofaspirin, as desired for specific treatment of subjects in need ofanalgesia. In one embodiment, the amount of aspirin is in a range offrom 500 to 600 milligrams, in a 2 gram dose form (dry solids) suitablefor quick dissolution in aqueous medium.

The amount of surfactant utilized in the compositions of the presentdisclosure is extremely low in comparison to other soluble aspirinformulations of the prior art. In compositions of the presentdisclosure, the amount of surfactant typically is below 0.10% by weight,based on total weight (dry solids weight) of the granules in the solubleaspirin composition, and may be as low as 0.016 to 0.018 weight percent,or lower, on the same dry solids weight basis.

In another illustrative embodiment, the soluble aspirin composition ofthe disclosure contains 650 milligrams aspirin, 350 milligrams citricacid in large crystal form, 1,000 milligrams of heat-treated potassiumbicarbonate, Sucralose™ sweetener, vanillin and flavor ingredients.

The soluble aspirin composition of the disclosure is an effervescing,bicarbonate salt-based solubilizable aspirin that typically dissolves inwater or other aqueous medium in less than 30 seconds, to constitute aready-to-drink dose. The dry solids composition in use is added to anappropriate amount of water or other aqueous medium, e.g., 2 or moreounces of cold water. Warm water may also be employed, and the rate ofdissolution of the dry solids composition of the disclosure increaseswith increasing temperature of the aqueous medium. When water iscombined with the composition, a chemical reaction takes place involvingreaction of the aspirin, bicarbonate salt, andpharmaceutically-acceptable acid ingredients. This reaction converts theingredients into an acetylsalicylate compound of the bicarbonate saltcation (e.g., potassium acetylsalicylate in the case of potassiumbicarbonate as the bicarbonate salt), and the acetylsalicylate compoundimmediately dissolves in water, leaving little or no undissolvedresidue.

The soluble aspirin composition of the present disclosure achieves asubstantial advance over the soluble aspirin composition of my U.S. Pat.No. 5,723,453, in respect of taste, rate and extent of dissolution, andease of use characteristics. Whereas a composition of my prior patentmay require 10 minutes to achieve near-complete dissolution, withresidual undissolved particles remaining at the surface of the aqueousmedium and significant residue at the bottom of the liquid volume,compositions of the present disclosure typically dissolve withoutstirring or agitation, in less than 60 seconds, e.g., in 30 seconds orless, with high rate reaction effecting dissolution in as little as oneounce of water for the aforementioned 2 gram dose of the dry solidscomposition, and with no residue or floating solids. The resultingsoluble aspirin aqueous formulation is characterized by an absence ofpowder solids.

The soluble aspirin composition of the present disclosure is formulatedso that all aspirin is bound to particles of bicarbonate, i.e., thecomposition contains no non-agglomerated aspirin. The granules,containing aspirin, powdered heat-treated bicarbonate salt, resin andsurfactant, are in mixture with crystalline particles ofpharmaceutically-acceptable acid, such as citric acid, and crystallineparticles of heat-treated bicarbonate salt, e.g., potassium bicarbonate.When the soluble aspirin composition is introduced to water or otheraqueous medium, the pharmaceutically acceptable acid crystals and theheat-treated bicarbonate salt crystals strongly react with one anotherto effect effervescence and mixing of the composition in the liquidvolume, and the pharmaceutically acceptable acid crystals react with theheat-treated bicarbonate salt in the granules to reactively break up anddisperse the granules, with the reaction involving the aspirin in thegranules, to yield potassium acetylsalicylate, which immediatelydissolves in the aqueous medium without residue.

The granules (containing aspirin, powdered heat-treated bicarbonatesalt, resin and surfactant) by themselves would dissolve in the aqueousmedium to which the granules are introduced, but the presence of theacid crystals and bicarbonate salt crystals greatly accelerate andenhance such dissolution so that the granules undergo reactivefragmentation, exposing more granule surface, which then reacts toeffect further fragmentation and breakup of the initial granulefragments, etc., so that an extremely rapid dissolution of the aspirinis effected.

The soluble aspirin compositions of the present disclosure achieve asignificant advance in the art, in that complete dissolution of thesolid particulate composition is achieved in less than 60 seconds withno residue. Further, in contrast to the formulations of Galat U.S. Pat.No. 5,107,030, which require substantial change of pH in aqueous mediumto effect any dissolution whatsoever, the compositions of the presentdisclosure are dissolved without significant change of pH. Further, theformulations of the Galat patent have been rigorously evaluated andtested by the present inventor for a period in excess of six months,without success in reproducing the results stated in such patent.Specifically, the present inventor was unable to effect any substantialdegree of dissolution by the teachings of such patent, without additionof excessive amounts of surfactant and alteration of pH.

The soluble aspirin composition of the present disclosure hasapplication to the treatment of headache, migraine, rheumatic pains,neuralgia, period pain, toothache and symptoms of colds and influenza.

The features and advantages of the disclosure are more fully shown bythe following non-limiting examples, wherein all parts and percentagesare by weight, unless otherwise expressly stated.

EXAMPLE 1

An analgesic composition of the disclosure, according to one embodimentthereof, is formulated to include the following ingredients:

-   potassium bicarbonate, USP granular-   potassium bicarbonate, USP milled to 250 mesh or smaller particle    size powder-   aspirin, USP milled to 325 mesh size-   sweetener, Sucralose™ or Aspartame™ sweetener-   spray dried flavors, oil-free, and pre-dried to less than 0.5%    moisture content-   citric acid anhydrous, USP large crystalline size, 10 mesh,    pre-dried to less than 0.01% moisture content-   flavoring and taste masking of potassium bicarbonate, vanillin    crystals, milled to 150 mesh-   caffeine-   surfactant, sodium laurel sulfate-   carrier resin, polyvinyl pyrrolidone (PVP K-30), pre-dried to less    than 0.5% moisture content-   alcohol, 99.9% USP grade isopropyl alcohol

The foregoing raw materials may be pretreated, with the Sucralose™sweetener, spray-dried oil-free flavors, vanillin, polyvinyl pyrrolidoneand citric acid being pre-dried to a moisture content of less than 0.5%by weight, if not already dry to such extent. All material is delumpedand screened. Potassium bicarbonate granular and potassium bicarbonatepowdered are heat treated to raise pH level thereof to a suitable value,e.g., a pH in a range of 9 to 9.5. The polyvinyl pyrrolidone andsurfactant are dissolved in a minimum amount of isopropyl alcohol, e.g.,utilizing 6 mL of isopropanol per gram of PVP, so that the resultingcomposition can be introduced into a granulation device to form thegranules of the composition. In one embodiment, the Sucralose™ sweetenercan be introduced to the polyvinyl pyrrolidone and isopropanol to forman additive composition. In other embodiments, surfactant may be addedto the polyvinyl pyrrolidone and isopropanol, and the resultingcomposition then may be spray-dried to provide an additive mixture forblending in the formulation.

The machinery used for processing and packaging of the productcomposition include a twin cone vacuum rotating dryer with a workingcapacity of 5-10 cubic feet and a bulk density rating of at least 100pounds per cubic foot. This dryer has a capability of 30 revolutions perhour and a jacket capable of maintaining a temperature of 130° C. AFreewitt or equivalent oscillating granulator is employed, and millingof potassium bicarbonate is carried out using a Co-Mill or a Fitz mill.Additional apparatus for processing the formulation include sealablestorage containers, a supply of steam or hot oil, a vacuum pump fordrying, a pH meter and scales.

In the granulation operation, a high or low shear granulator/vacuumdryer can be employed, e.g., a granulator/vacuum dryer having a 200liter working capacity. Alternatively, a closed circuit fluid bedgranulator/dryer can be employed, having solvent recovery capability. Aperistaltic pump liquid binder delivery system is utilized, with a 10gallon capacity binder mixing tank and agitator. Hot water for drying isprovided at a temperature of approximately 140° F.

Pre-blending operations involved in the manufacturing procedure arecarried out with a Twin Cone blender of suitable capacity, e.g. 10 cubicfeet working capacity. Final blending is performed with a Twin Coneslant cone blender or a Munson pharmaceutical grade blender ofappropriate capacity, e.g., about 80 cubic feet.

The granulation method utilizes aspirin with a particle size of 325mesh, and heat-treated potassium bicarbonate having a particle size of250 mesh, as well as surfactant, dried polyvinyl pyrrolidone and highpurity isopropyl alcohol.

In the granulation process, milled 250 mesh heat treated potassiumbicarbonate, 325 mesh aspirin and optionally caffeine are introducedinto a high shear Zanchetta mixer.

The polyvinyl pyrrolidone and the surfactant are dissolved in the highpurity isopropanol to form a binder solution.

During granulation, with choppers and mixing blade set at an appropriatespeed, the binder solution containing polyvinyl pyrrolidone andsurfactant is added completely and the resulting mixture is run untilcorrect size and density of granules is achieved, typically less than 10minutes. The objective of this granulation operation is to make thegranulation particle size as small as possible while achieving maximumdensity. When the granulation operation is complete, the high shearmixer is set into rotating motion, and heat and vacuum are supplieduntil granulation particles are dried down to 0.2% or lower moisturecontent. The dried granulation product then is sized by passage througha Co-Mill to a particle size of 40-60 mesh, and stored in sealedstainless storage bins.

In the final blending operation, the granulation is mixed with flavors,sweetener and heat-treated potassium bicarbonate. Flavors, Sucralose™sweetener and citric acid granules are delumped and preblended togetherbefore final blending. The final product blend contains the preblendgranulation and additional heat-treated granules of potassiumbicarbonate. The final product blend is introduced to stainless steel,humidity-proof vacuum containers maintained under continuous vacuum.

Packaging is carried out under nitrogen purging, into sealed stickpacks, using vertical form/fill/seal stick packaging machines equippedwith a nitrogen purge, and conventional box packaging and case packagingequipment.

The amount of aspirin in the final composition product is 650milligrams, in a ˜2 gram dose form (dry solids) for subsequentdissolution in aqueous medium, and the final composition productadditionally contains 350 milligrams citric acid in large crystal form,300-400 milligrams of free-form (non-agglomerate) potassium bicarbonate,and Sucralose™ sweetener, vanillin and flavor ingredients, with asuitable amount of surfactant below 0.1 weight percent, e.g., 0.016 to0.018 weight percent sodium laurel sulfate, based on the weight of thegranules, and polyvinyl pyrrolidone being present at a suitableconcentration, e.g., in a range of from 1.8 to 2 percent by weight,based on the weight of the granules. In general, the total amount ofpotassium bicarbonate in the composition, including both granules andfree-form, is in a range of from 700 to 1500 mg. The composition may forexample contain the aforementioned 300-400 mg of free-form heat-treatedpotassium bicarbonate, and approximately 700 mg heat-treated potassiumbicarbonate in the granules. The formulated product is granulated sothat it is non-floating as regards the constituent particles, e.g., in aparticle size range of from 40-60 mesh. The flavor ingredients areessentially completely oil-free in character, in order to provide rapidsolubilization of the effervescent, potassium-based soluble aspirincomposition.

EXAMPLE 2

The ˜2 gram dose form soluble aspirin composition of EXAMPLE 1 dissolvesin water in less than 30 seconds to constitute a ready to drink dose,when added to 2 ounces of cold water. Upon combination of the dry solidscomposition with water, a chemical reaction takes place that reacts theaspirin, potassium bicarbonate and citric acid, to yield potassiumacetylsalicylate. The potassium acetylsalicylate immediately dissolvesin water, leaving no undissolved residue.

While the disclosure has been has been set out herein in reference tospecific aspects, features and illustrative embodiments, it will beappreciated that the utility of the disclosure is not thus limited, butrather extends to and encompasses numerous other variations,modifications and alternative embodiments, as will suggest themselves tothose of ordinary skill in the field of the present disclosure, based onthe description herein. Correspondingly, the invention as hereinafterclaimed is intended to be broadly construed and interpreted, asincluding all such variations, modifications and alternativeembodiments, within its spirit and scope.

What is claimed is:
 1. A soluble aspirin composition, comprising: (i)granules including aspirin, heat-treated bicarbonate salt,pharmaceutically-acceptable resin and surfactant, in mixture with: (ii)crystalline particles of pharmaceutically-acceptable acid; and (iii)crystalline particles of heat-treated bicarbonate salt; wherein thesoluble aspirin composition when introduced to water undergoes reactionof the crystalline particles of pharmaceutically-acceptable acid withthe heat-treated bicarbonate salt and the aspirin to effect effervescingaction and disintegration of the granules, with conversion of theaspirin to an acetylsalicylate compound of the bicarbonate salt cation,so that the composition rapidly dissolves in the water, withoutoccurrence of undissolved residue.
 2. The soluble aspirin composition ofclaim 1, wherein the bicarbonate salt comprises one or more of potassiumbicarbonate, sodium bicarbonate, calcium bicarbonate, magnesiumcarbonate and lithium carbonate.
 3. The soluble aspirin composition ofclaim 1, wherein aspirin is present at a concentration of from 50 to2000 mg.
 4. The soluble aspirin composition of claim 1, wherein theheat-treated bicarbonate salt comprises heat-treated potassiumbicarbonate having a pH in a range of from 8.4 to
 10. 5. The solubleaspirin composition of claim 1, wherein the pharmaceutically-acceptableresin is selected from the group consisting of polyvinyl pyrrolidone,polyvinyl alcohol, acrylic acid polymers, methacrylic acid polymers,sulfonated styrenes, sulfonated dimethyl benzenes, modified celluloses,and dextrans.
 6. The soluble aspirin composition of claim 1, wherein thepharmaceutically-acceptable resin comprises polyvinyl pyrrolidone. 7.The soluble aspirin composition of claim 1, wherein thepharmaceutically-acceptable resin has a concentration in a range of fromabout 1.5 to about 4 percent by weight, based on total weight of thegranules.
 8. The soluble aspirin composition of claim 1, wherein thepharmaceutically-acceptable acid is selected from the group consistingof citric acid, acetic acid, adipic acid, benzoate acid, caproic acid,malic acid, malonic acid, nicotinic acid, lauric acid, glycolic acid,oxalic acid, phosphoric acid, succinic acid, oleic acid, palmitic acid,proprionic acid, cinnamic acid, gluconic acid, stearate acid, andtartaric acid.
 9. The soluble aspirin composition of claim 1, whereinthe surfactant is selected from the group consisting of sodium laurelsulfate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitanmonooleate, polyethylene glycol 300, propoxylated polyethylene glycol,polyoxyethylene lauryl ether, and diethylene glycol monoethyl ether. 10.The soluble aspirin composition of claim 1, wherein the surfactantcomprises sodium laurel sulfate at a concentration in a range of from0.01 to 0.1 weight percent, based on total weight of the granules. 11.The soluble aspirin composition of claim 1, further comprising at leastone ingredient selected from the group consisting of flavorants,sweeteners, acetaminophen and caffeine.
 12. The soluble aspirincomposition of claim 1, oil-free in character, and having a moisturecontent less than 0.5% by weight, based on total weight of thecomposition.
 13. A dry solids aspirin composition, comprising: (i)granules including aspirin, heat-treated potassium bicarbonate,pharmaceutically-acceptable resin and surfactant, in mixture with: (ii)crystalline particles of pharmaceutically-acceptable acid; and (iii)crystalline particles of heat-treated potassium bicarbonate.
 14. The drysolids aspirin composition of claim 13, wherein aspirin is present at aconcentration of from 50 to 2000 mg.
 15. The dry solids aspirincomposition of claim 13, wherein pH of the heat-treated potassiumbicarbonate is in a range of from 8.4 to
 10. 16. The dry solids aspirincomposition of claim 14, wherein the pharmaceutically-acceptable resincomprises polyvinyl pyrrolidone.
 17. The dry solids aspirin compositionof claim 16, wherein the pharmaceutically-acceptable resin has aconcentration in a range of from about 1.5 to about 4 percent by weight,based on total weight of the granules.
 18. The dry solids aspirincomposition of claim 13, wherein the pharmaceutically-acceptable acidcomprises citric acid.
 19. The dry solids aspirin composition of claim13, further comprising at least one ingredient selected from the groupconsisting of flavorants, sweeteners, acetaminophen and caffeine. 20.The dry solids aspirin composition of claim 13, oil-free in character,and having a moisture content less than 0.5% by weight, based on totalweight of the composition.
 21. A soluble aspirin composition,comprising: (i) granules including aspirin, heat-treated bicarbonatesalt and pharmaceutically-acceptable resin, in mixture with: (ii)crystalline particles of pharmaceutically-acceptable acid; and (iii)crystalline particles of heat-treated bicarbonate salt; wherein thesoluble aspirin composition when introduced to water undergoes reactionof the crystalline particles of pharmaceutically-acceptable acid withthe heat-treated bicarbonate salt and the aspirin to effect effervescingaction and disintegration of the granules, with conversion of theaspirin to an acetylsalicylate compound of the bicarbonate salt cation,so that the composition rapidly dissolves in the water in less thanabout 60 seconds.
 22. The soluble aspirin composition of claim 21,wherein the granules further comprise a surfactant.
 23. The solubleaspirin composition of claim 22, wherein the composition rapidlydissolves in the water in less than about 30 seconds.
 24. A method ofmaking a soluble aspirin composition, comprising: agglomerating powderedaspirin and powdered heat-treated bicarbonate salt with apharmaceutically-acceptable resin, to form granules; and mixing thegranules with crystalline particles of pharmaceutically-acceptable acidand crystalline particles of heat-treated bicarbonate salt, to yield thesoluble aspirin analgesic composition.
 25. The method of claim 24,wherein the granules further include a surfactant.
 26. A method ofproviding aspirin treatment to a subject in need thereof, comprisingmixing an effective amount of the dry solids aspirin composition ofclaim 13 with a solubilizing quantity of aqueous medium, to produce asolubilized aspirin solution, and administering said solubilized aspirinsolution to said subject.